This proposal describes a 5 year training program for the development of an academic career in the basis sciences. The principal investigator has completed his training in Pediatrics and sub-specialty training in Pediatric Pulmonology at the University of Iowa and now is focusing on developing his basic science knowledge and laboratory experience to become an independent investigator. This program involves pulmonary innate immune factors and how they interact with bacterial pathogens. Dr. Paul McCray will mentor the principal investigator's scientific development. Dr. McCray is a recognized leader in the field of pulmonary innate immunity with emphasis on the role of antimicrobial peptides such as the beta-defensins. Dr. Michael Apicella will act as co-mentor. He is the Department Head of Microbiology at The University of Iowa and is a renowned expert on Haemophilus influenzae. His work has focused on. the antigenic structure of Haemophilus membrane components and their relationship to disease. In addition, an advisory committee of highly-regarded medical scientists will provide scientific and career advice. Dr. Starner's research will investigate the interactions between pulmonary innate immune factors and nontypeable H. influenzae (NTHi), a common disease-associated pathogen in otitis media, COPD and cystic fibrosis. His recent work demonstrated that the hexaacylation of lipid A is an important determinant of the antimicrobial sensitivities toward specific beta-defensins. The proposed experiments will investigate outer membrane changes and potential binding sites of the beta-defensins on laboratory, mutant and clinical strains using microbiologic, biochemical, and sub-proteomic approaches. Two specific aims will be addressed: 1) identify the specific cell wall component(s) of NTHi that interact with human beta-defensins; and 2) determine the effects of human beta-defensin exposure on NTHi outer membrane protein and LOS expression. These will be the first studies on the interactions between NTHi and the beta-defensins. The University of Iowa provides an ideal environment for this proposal because of the Pediatrics and Microbiology Departments' strong track records in research and the outstanding mentors selected. This environment will maximize the potential for the principal investigator to establish himself in a basic science career as an academic independent investigator.